Showing papers by "Jason E. Gestwicki published in 2006"

Synthetic Multivalent Ligands as Probes of Signal Transduction

Abstract: Cell-surface receptors acquire information from the extracellular environment and coordinate intracellular responses Many receptors do not operate as individual entities, but rather as part of dimeric or oligomeric complexes Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades Understanding the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication is critical; chemical synthesis can provide compounds to address the role of receptor assembly in signal transduction Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements This Review focuses on the use of synthetic multivalent ligands to characterize receptor function

Synthetische multivalente Liganden als Sonden fÜr die Signaltransduktion

Abstract: Zelloberflachenrezeptoren nehmen Informationen aus der extrazellularen Umgebung auf und stimmen die intrazellularen Reaktionen darauf ab. Viele dieser Rezeptoren agieren nicht einzeln, sondern als Teil von dimeren oder oligomeren Komplexen. Die funktionelle Kopplung mehrerer Rezeptoren verleiht den Signaltransduktionswegen moglicherweise die Empfindlichkeit, die fur die Regulation zellularer Reaktionen erforderlich ist. Auserdem konnen Multirezeptor-Signalkomplexe ansonsten uberlappende Signalkaskaden raumlich trennen. Die Mechanismen, das Ausmas und die Konsequenzen der Colokalisation und die Kommunikation zwischen den Rezeptoren sind noch unklar, doch synthetische Verbindungen konnen dabei helfen, die Rolle der Rezeptorassoziationen bei der Signaltransduktion zu ermitteln. Solche multivalenten Liganden konnen Bindestellen verschiedener Grose, Form, Valenz, Orientierung und raumlicher Anordnung enthalten. Der Schwerpunkt dieses Aufsatzes liegt auf dem Einsatz synthetischer multivalenter Liganden, um die Rezeptorfunktion zu charakterisieren.

Synthetic Multivalent Ligands as Probes of Signal Transduction

Abstract: Cell-surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Many receptors do not operate as individual entities, but rather as part of dimeric or oligomeric complexes. Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Understanding the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication is critical; chemical synthesis can provide compounds to address the role of receptor assembly in signal transduction. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. This Review focuses on the use of synthetic multivalent ligands to characterize receptor function.

Improving the pharmacokinetics of protease inhibitors and other drugs

Abstract: A method for modulating at least one pharmacokinetic property of a protease inhibitor upon administration to a host is provided. One administers to the host an effective amount of a bifunctional compound of less than about 5000 daltons comprising the protease inhibitor or an active derivative thereof and a pharmacokinetic modulating moiety. The pharmacokinetic modulating moiety binds to at least one intracellular protein. The bifunctional compound has at least one modulated pharmacokinetic property upon administration to the host as compared to a free drug control that comprises the protease inhibitor.

Methods of screening bifunctional molecules for modulated pharmacokinetic properties

Abstract: Methods for screening bifunctional molecules of a drug of interest for modulated pharmacokinetic properties are provided. The subject methods include combining in a reaction mixture a metabolizer of the drug of interest, a reporter of activity of the metabolizer; and a bifunctional compound of the drug of interest. Signal from the reporter is then evaluated to determine whether the bifunctional compound has a modulated pharmacokinetic property as compared to a free drug control. Also provided are kits and devices for practicing the subject methods of the invention.

Reclamation of proteins from the cellular scrap heap.

Abstract: A growing number of diseases have been associated with protein misfolding. Thus, strategies that use small molecules to adjust folding tendencies have therapeutic potential. However, progress in this area has been hampered by an insufficient description of the molecular underpinnings of protein instability within the cell. In a recent report, a chemical approach was taken to probe the mechanism by which Gaucher disease associated mutations in glucocerebrosidase destabilize that enzyme and lead to its destruction. These studies provide a blueprint for the design of "chemical chaperones" for the exploration of cellular protein homeostasis and the treatment of misfolding diseases.